Sindbis virus is an alphavirus that is transmitted by mosquitoes to animal and human hosts in many geographical locations worldwide. Although Sindbis virus is a relatively mild human pathogen, it causes mild to severe encephalitis and mortality in mice, thereby serving as a model for related human encephalitis viruses. We demonstrated that Sindbis virus induces apoptosis of cultured neurons and in neurons of the brain. Furthermore, we found that mammalian Bcl-2 family proteins and other regulators of cell death have a significant impact on the outcome of a Sindbis virus infection. These studies led to unexpected findings for both the cell and the virus. The goals of this proposal are to understand how cellular regulators of programmed cell death alter the response of neurons to Sindbis virus infection, resulting in acute virus induced neuronal death or long-term persistence. By using Sindbis virus as a vector for gene delivery to neurons of the brain, in combination with knockout mice, we propose to determine how pro-apoptotic Bcl-2 family proteins Bax, Bak and BAD alter viral pathogenesis. We suggest that Bax, Bak and BAD decrease neuronal excitability by regulating mitochondrial functions, resulting in the unexpected effect of protecting neurons and mice from Sindbis virus-induced death and excitotoxic damage. The strategy is to explore the role of Bax, Bak and BAD in neuronal excitability (Aim 1), to link the role of Bax and Bak in regulating synaptic activity to their effects on Sindbis virus infections (Aim 2), and to explore new mechanisms by which host factors suppress viral replication and pro-death functions in mature neurons, leading to the establishment of a persistent infection (Aim 3).